Progesterone withdrawal increases immobility behavior of mice in a rodent model of depression. The overarching goal of the research proposed in this application is to understand how progesterone withdrawal increases immobility behavior. I hypothesize that peripheral progesterone withdrawal and a correlated decrease in neural allopregnanolone (ALLO) levels, a GABAergic progesterone metabolite, result in increased neural activity in discrete brain regions, that GABA-A receptor function is decreased in one or more of these brain regions (corresponding to the increase in activity), and that pharmacological GABA-A receptor blockade can increase immobility behavior. Progesterone withdrawal is accomplished by giving high-physiological levels of exogenous progesterone for 5 days and terminating exogenous administration. ALLO withdrawal is accomplished by first administering progesterone, then co-administering progesterone and the 5alpha-reductase inhibitor finasteride, which blocks the conversion of progesterone to ALLO. Studies related to Specific Aim 1 will use c-Fos immunohistochemistry to investigate neuronal activity in the hippocampus, amygdala, and other brain areas during progesterone and ALLO withdrawal. Studies related to Specific Aim 2 will use the progesterone receptor antagonist onapristone and the GABA-A receptor antagonist picrotoxin to test whether progesterone receptor or GABA-A receptor blockade, alone or in combination, increase immobility behavior. Studies related to Specific Aim 3 will determine whether progesterone withdrawal and ALLO withdrawal decrease GABA-A function, as measured by GABA-stimulated chloride flux in hippocampal microsacs.[unreadable] Public Health Relevance: Progesterone withdrawal has been suggested to underlie psychiatric disorders such as premenstrual syndrome (or premenstrual dysphoric disorder) and postpartum depression. Previous research provides strong evidence that mice may serve as appropriate model organisms to study the neurological changes associated with progesterone withdrawal. It is hoped that identifying the effects of progesterone withdrawal will lead to better understanding, diagnosis, and treatments of premenstrual syndrome and postpartum depression.[unreadable] Plain language summary: Many women feel depressed following childbirth or during their menstrual cycles, even though nothing is outwardly wrong. Pregnancy and the menstrual cycle cause changes in the hormone progesterone that may be affecting the brain. Understanding how the brain is affected by progesterone will hopefully lead to improved treatments for these women.[unreadable]